David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Nat Commun. 2022 Aug 17;13(1):4829. doi: 10.1038/s41467-022-31859-3.
Despite therapeutic advancements, oral cavity squamous cell carcinoma (OCSCC) remains a difficult disease to treat. Systemic platinum-based chemotherapy often leads to dose-limiting toxicity (DLT), affecting quality of life. PRV111 is a nanotechnology-based system for local delivery of cisplatin loaded chitosan particles, that penetrate tumor tissue and lymphatic channels while avoiding systemic circulation and toxicity. Here we evaluate PRV111 using animal models of oral cancer, followed by a clinical trial in patients with OCSCC. In vivo, PRV111 results in elevated cisplatin retention in tumors and negligible systemic levels, compared to the intravenous, intraperitoneal or intratumoral delivery. Furthermore, PRV111 produces robust anti-tumor responses in subcutaneous and orthotopic cancer models and results in complete regression of carcinogen-induced premalignant lesions. In a phase 1/2, open-label, single-arm trial (NCT03502148), primary endpoints of efficacy (≥30% tumor volume reduction) and safety (incidence of DLTs) of neoadjuvant PRV111 were reached, with 69% tumor reduction in ~7 days and over 87% response rate. Secondary endpoints (cisplatin biodistribution, loco-regional control, and technical success) were achieved. No DLTs or drug-related serious adverse events were reported. No locoregional recurrences were evident in 6 months. Integration of PRV111 with current standard of care may improve health outcomes and survival of patients with OCSCC.
尽管治疗方法有所进步，但口腔鳞状细胞癌（OCSCC）仍然是一种难以治疗的疾病。全身铂类化疗常常导致剂量限制毒性（DLT），影响生活质量。PRV111 是一种基于纳米技术的系统，用于局部递送电载顺铂的壳聚糖颗粒，可穿透肿瘤组织和淋巴通道，同时避免全身循环和毒性。在这里，我们使用口腔癌动物模型评估了 PRV111，随后在 OCSCC 患者中进行了临床试验。在体内，与静脉、腹腔内或肿瘤内给药相比，PRV111 导致肿瘤中顺铂的保留增加，而系统水平降低。此外，PRV111 在皮下和原位癌症模型中产生了强大的抗肿瘤反应，并导致致癌物诱导的癌前病变完全消退。在一项 1/2 期、开放标签、单臂试验（NCT03502148）中，新辅助 PRV111 的主要疗效终点（≥30%肿瘤体积缩小）和安全性（DLT 发生率）达到了，约 7 天内肿瘤缩小 69%，缓解率超过 87%。次要终点（顺铂生物分布、局部区域控制和技术成功）也达到了。没有报告 DLT 或与药物相关的严重不良事件。6 个月内无局部区域复发。将 PRV111 与当前的标准治疗方法相结合，可能会改善 OCSCC 患者的健康结果和生存率。
